Mitsuhiko Kawashima

Proton Beam Therapy for Unresectable Malignancies of the Nasal Cavity and Paranasal Sinuses

PURPOSE The cure rate for unresectable malignancies of the nasal cavity and paranasal sinuses is low. Because irradiation with proton beams, which are characterized by their rapid fall-off at the distal end of the Bragg peak and sharp lateral penumbra, depending on energy, depth, and delivery, provide better dose distribution than X-ray irradiation, proton beam therapy (PBT) might improve treatment outcomes for conditions located in proximity to risk organs. We retrospectively analyzed the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS We reviewed 39 patients in our database fulfilling the following criteria: unresectable malignant tumors of the nasal cavity, paranasal sinuses or skull base; N0M0 disease; and treatment with PBT (>60 GyE) from January 1999 to December 2006. RESULTS Median patient age was 57 years (range, 22-84 years); 22 of the patients were men and 17 were women. The most frequent primary site was the nasal cavity (n=26, 67%). The local control rates at 6 months and 1 year were 84.6% and 77.0%, respectively. With a median active follow-up of 45.4 months, 3-year progression-free and overall survival were 49.1% and 59.3%, respectively. The most common acute toxicities were mild dermatitis (Grade 2, 33.3%), but no severe toxicity was observed (Grade 3 or greater, 0%). Five patients (12.8%) experienced Grade 3 to 5 late toxicities, and one treatment-related death was reported, caused by cerebrospinal fluid leakage Grade 5 (2.6%). CONCLUSION These findings suggest that the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses make it is a promising treatment option.

Multi-institutional Analysis of Solitary Extramedullary Plasmacytoma of the Head and Neck Treated with Curative Radiotherapy

PURPOSE The purpose of this study was to elucidate the efficacy and optimal method of radiotherapy in the management of solitary extramedullary plasmacytoma occurring in the head and neck regions (EMPHN). METHODS AND MATERIALS Sixty-seven patients (43 male and 24 female) diagnosed with EMPHN between 1983 and 2008 at 23 Japanese institutions were reviewed. The median patient age was 64 years (range, 12-83). The median dose administered was 50 Gy (range, 30-64 Gy). Survival data were calculated by the Kaplan-Meier method. RESULTS The median follow-up duration was 63 months. Major tumor sites were nasal or paranasal cavities in 36 (54%) patients, oropharynx or nasopharynx in 16 (23%) patients, orbita in 6 (9%) patients, and larynx in 3 (5%) patients. The 5- and 10-year local control rates were 95% and 87%, whereas the 5- and 10-year disease-free survival rates were 56% and 54%, respectively. There were 5 (7.5%), 12 (18%), and 8 (12%) patients who experienced local failure, distant metastasis, and progression to multiple myeloma, respectively. In total, 18 patients died, including 10 (15%) patients who died due to complications from EMPHN. The 5- and 10-year overall survival (OS) rates were 73% and 56%, respectively. Radiotherapy combined with surgery was identified as the lone significant prognostic factor for OS (p = 0.04), whereas age, gender, radiation dose, tumor size, and chemotherapy were not predictive. No patient experienced any severe acute morbidity. CONCLUSIONS Radiotherapy was quite effective and safe for patients with EMPHN. Radiotherapy combined with surgery produced a better outcome according to survival rates. These findings require confirmation by further studies with larger numbers of patients with EMPHN.

Proton Beam Therapy as a Nonsurgical Approach to Mucosal Melanoma of the Head and Neck: A Pilot Study

PURPOSE The aim of this pilot study was to assess the clinical benefit of proton beam therapy for mucosal melanoma of the head and neck. METHODS AND MATERIALS Patients with mucosal melanoma of the head and neck with histologically confirmed malignant melanoma and N0 and M0 disease were enrolled. Proton therapy was delivered three times per week with a planned total dose of 60 Gy equivalents (GyE) in 15 fractions. RESULTS Fourteen consecutive patients were enrolled from January 2004 through February 2008. Patient characteristics were as follows: median age 73 years old (range, 56 to 79 years); male/female ratio, 7/7; and T stage 1/2/3/4, 3/2/0/9. All patients were able to receive the full dose of proton therapy. The most common acute toxicities were mucositis (grade 3, 21%) and mild dermatitis (grade 3, 0%). As for late toxicity, 2 patients had a unilateral decrease in visual acuity, although blindness did not occur. No treatment-related deaths occurred throughout the study. Initial local control rate was 85.7%, and, with a median follow-up period of 36.7 months, median progression-free survival was 25.1 months, and 3-year overall survival rates were 58.0%. The most frequent site of first failure was cervical lymph nodes (6 patients), followed by local failure in 1 patient and lung metastases in 1 patient. On follow-up, 5 patients died of disease, 4 died due to cachexia caused by distant metastases, and 1 patient by carotid artery perforation cause by lymph nodes metastases. CONCLUSIONS Proton beam radiotherapy showed promising local control benefits and would benefit from ongoing clinical study.

Apparent absence of a proton beam dose rate effect and possible differences in RBE between Bragg peak and plateau

PURPOSE Respiration-gated irradiation for a moving target requires a longer time to deliver single fraction in proton radiotherapy (PRT). Ultrahigh dose rate (UDR) proton beam, which is 10-100 times higher than that is used in current clinical practice, has been investigated to deliver daily dose in single breath hold duration. The purpose of this study is to investigate the survival curve and relative biological effectiveness (RBE) of such an ultrahigh dose rate proton beam and their linear energy transfer (LET) dependence. METHODS HSG cells were irradiated by a spatially and temporally uniform proton beam at two different dose rates: 8 Gy/min (CDR, clinical dose rate) and 325 Gy/min (UDR, ultrahigh dose rate) at the Bragg peak and 1.75 (CDR) and 114 Gy/min (UDR) at the plateau. To study LET dependence, the cells were positioned at the Bragg peak, where the absorbed dose-averaged LET was 3.19 keV/microm, and at the plateau, where it was 0.56 keV/microm. After the cell exposure and colony assay, the measured data were fitted by the linear quadratic (LQ) model and the survival curves and RBE at 10% survival were compared. RESULTS No significant difference was observed in the survival curves between the two proton dose rates. The ratio of the RBE for CDR/UDR was 0.98 +/- 0.04 at the Bragg peak and 0.96 +/- 0.06 at the plateau. On the other hand, Bragg peak/plateau RBE ratio was 1.15 +/- 0.05 for UDR and 1.18 +/- 0.07 for CDR. CONCLUSIONS Present RBE can be consistently used in treatment planning of PRT using ultrahigh dose rate radiation. Because a significant increase in RBE toward the Bragg peak was observed for both UDR and CDR, further evaluation of RBE enhancement toward the Bragg peak and beyond is required.

Radiotherapy for hepatocellular carcinoma

Purpose: To retrospectively evaluate the effectiveness of radiotherapy with or without transarterial embolization (TAE) and/or percutaneous ethanol injection (PEI) in patients with hepatocellular carcinoma who were ineligible for surgery. Patients and Methods: From October 1984 to November 1997, 62 patients underwent radiotherapy receiving 50 to 70 Gy in 25 to 35 treatments with or without transarterial embolization and/or percutaneous ethanol injection and were followed for a median period of 8.6 months (1.5 to 92 months). Results: Overall median survival rates were 9.5 months. Significant prognostic factors were the extent of pretreatment liver function impairment, radiation field size and the existence of tumor thrombosis. Six-month and 1-year local control rates were 67 and 54%, respectively. Seven of the 8 patients who suffered from hepatic failure had poor pretreatment liver functions. Conclusion: Radiotherapy with or without transarterial embolization and/or percutaneous ethanol injection appears effective in controlling hepatocellular carcinoma and prolonged survival. Individualized treatment strategies are presented depending on the tumor presentation and the degree of liver function impairment.Hintergrund: Retrospektive Evaluierung der Wirksamkeit einer Bestrahlung mit oder ohne transarterielle Embolisation oder perkutaner Alkoholinjektion bei Patienten mit inoperablem hepatozellulärem Karzinom. Patienten und Methodik: Von Oktober 1984 bis November 1997 wurden 62 Patienten mit einer Gesamtdosis von 50 bis 70 Gy in 25 bis 35 Fraktionen mit oder ohne transarterielle Embolisation oder perkutane Alkoholinjektion behandelt. Der mediane Follow-up betrug 8,6 Monate (1,5 bis 92 Monate). Ergebnisse: Das mediane Gesamtüberleben betrug 9,5 Monate. Signifikante prognostische Einflussfaktoren waren das Ausmaß der prätherapeutischen Leberfunktionseinschränkung, die Bestrahlungsfeldgröße und das Vorhandensein von Tumorthrombosen. Nach sechs Monaten betrug die lokale Kontrolle 67%, nach einem Jahr 54%. Sieben der acht Patienten, die ein Leberversagen erlitten, hatten eine schlechte prätherapeutische Leberfunktion. Schlussfolgerung: Die Bestrahlung mit oder ohne transarterielle Embolisation und/oder perkutane Alkoholinjektion scheint bei der Behandlung des hepatozellulären Karzinoms wirksam zu sein und verlängert das Überleben. Individualisierte Behandlungsstrategien, abhängig von der Tumorpräsentation und dem Ausmaß der Leberfunktionseinschränkung, werden vorgestellt.

Proton dose distribution measurements using a MOSFET detector with a simple dose-weighted correction method for LET effects

We experimentally evaluated the proton beam dose reproducibility, sensitivity, angular dependence and depth‐dose relationships for a new Metal Oxide Semiconductor Field Effect Transistor (MOSFET) detector. The detector was fabricated with a thinner oxide layer and was operated at high‐bias voltages. In order to accurately measure dose distributions, we developed a practical method for correcting the MOSFET response to proton beams. The detector was tested by examining lateral dose profiles formed by protons passing through an L‐shaped bolus. The dose reproducibility, angular dependence and depth‐dose response were evaluated using a 190 MeV proton beam. Depth‐output curves produced using the MOSFET detectors were compared with results obtained using an ionization chamber (IC). Since accurate measurements of proton dose distribution require correction for LET effects, we developed a simple dose‐weighted correction method. The correction factors were determined as a function of proton penetration depth, or residual range. The residual proton range at each measurement point was calculated using the pencil beam algorithm. Lateral measurements in a phantom were obtained for pristine and SOBP beams. The reproducibility of the MOSFET detector was within 2%, and the angular dependence was less than 9%. The detector exhibited a good response at the Bragg peak (0.74 relative to the IC detector). For dose distributions resulting from protons passing through an L‐shaped bolus, the corrected MOSFET dose agreed well with the IC results. Absolute proton dosimetry can be performed using MOSFET detectors to a precision of about 3% (1 sigma). A thinner oxide layer thickness improved the LET in proton dosimetry. By employing correction methods for LET dependence, it is possible to measure absolute proton dose using MOSFET detectors. PACS number: 87.56.‐v

Evaluating positional accuracy using megavoltage cone-beam computed tomography for IMRT with head-and-neck cancer

Accurate dose delivery is essential for the success of intensity-modulated radiation therapy (IMRT) for patients with head-and-neck (HN) cancer. Reproducibility of IMRT dose delivery to HN regions can be critically influenced by treatment-related changes in body contours. Moreover, some set-up margins may not be adaptable to positional uncertainties of HN structures at every treatment. To obtain evidence for appropriate set-up margins in various head and neck areas, we prospectively evaluated positional deviation (δ values) of four bony landmarks (i.e. the clivus and occipital protuberance for the head region, and the mental protuberance and C5 for the neck region) using megavoltage cone-beam computed tomography during a treatment course. Over 800 δ values were analyzed in each translational direction. Positional uncertainties for HN cancer patients undergoing IMRT were evaluated relative to the body mass index. Low positional accuracy was observed for the neck region compared with the head region. For the head region, most of the δ was distributed within ±5 mm, and use of the current set-up margin was appropriate. However, the δ values for the neck region were within ±8 mm. Especially for overweight patients, a few millimeters needed to be added to give an adequate set-up margin. For accurate dose delivery to targets and to avoid excess exposure to normal tissues, we recommend that the positional verification process be performed before every treatment.

Impact of early radiological response evaluation on radiotherapeutic outcomes in the patients with nasal cavity and paranasal sinus malignancies

We analyzed the correlation between primary tumor response within 6 months after radiation therapy (RT) including proton beam therapy (PBT) and progression free survival rate (PFS) in patients with nasal cavity and paranasal sinus malignancies to clarify the impact of early radiological evaluation of treatment response on prognosis. Sixty-five patients treated between January 1998 and December 2008, and whose follow-up duration was more than 2 years were included. The Response Evaluation Criteria in Solid Tumors (version 1.1) was used for the evaluation of treatment. Median age was 59 years (range 21–83 years). Olfactory neuroblastoma (n = 20, 30%) and squamous cell carcinoma (n = 15, 23%) were the major pathological tumor types. The median follow-up duration was 51.6 months. Radiological response evaluation within 6 months after treatment demonstrated that 15% of the patients achieved complete response (CR), and 3-year progression free survival rates of all patients was 49.2%. The 3-year PFS rates according to response for the treatment were 55.6% in the patients with CR and 46.4% in those with non-CR, respectively (P = 0.643). However, the 3-year PFS rates were 80.% in the patients with CR and 10.% in those with non-CR (P = 0.051) in the patients with squamous cell carcinoma (SCC) histology. Radiological response evaluation within 6 months did not have a significant impact on prognosis when analysis included all histology, although early radiological response within 6 months after RT had a borderline significant impact on treatment outcomes for the patients with nasal and paranasal SCC.

In vivo proton dosimetry using a MOSFET detector in an anthropomorphic phantom with tissue inhomogeneity

When in vivo proton dosimetry is performed with a metal‐oxide semiconductor field‐effect transistor (MOSFET) detector, the response of the detector depends strongly on the linear energy transfer. The present study reports a practical method to correct the MOSFET response for linear energy transfer dependence by using a simplified Monte Carlo dose calculation method (SMC). A depth‐output curve for a mono‐energetic proton beam in polyethylene was measured with the MOSFET detector. This curve was used to calculate MOSFET output distributions with the SMC (SMCMOSFET). The SMCMOSFET output value at an arbitrary point was compared with the value obtained by the conventional SMCPPIC, which calculates proton dose distributions by using the depth‐dose curve determined by a parallel‐plate ionization chamber (PPIC). The ratio of the two values was used to calculate the correction factor of the MOSFET response at an arbitrary point. The dose obtained by the MOSFET detector was determined from the product of the correction factor and the MOSFET raw dose. When in vivo proton dosimetry was performed with the MOSFET detector in an anthropomorphic phantom, the corrected MOSFET doses agreed with the SMCPPIC results within the measurement error. To our knowledge, this is the first report of successful in vivo proton dosimetry with a MOSFET detector. PACS number: 87.56.‐v

Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition.

OBJECTIVE The objective of the study was to evaluate locoregional control after intensity-modulated radiotherapy for nasopharyngeal cancer using a target definition along with anatomical boundaries. METHODS Forty patients with biopsy-proven squamous cell or non-keratinizing carcinoma of the nasopharynx who underwent intensity-modulated radiotherapy between April 2006 and November 2009 were reviewed. There were 10 females and 30 males with a median age of 48 years (range, 17-74 years). More than half of the patients had T3/4 (n = 21) and/or N2/3 (n = 24) disease. Intensity-modulated radiotherapy was administered as 70 Gy/33 fractions with or without concomitant chemotherapy. The clinical target volume was contoured along with muscular fascia or periosteum, and the prescribed radiotherapy dose was determined for each anatomical compartment and lymph node level in the head and neck. RESULTS One local recurrence was observed at Meckels cave on the periphery of the high-risk clinical target volume receiving a total dose of <63 Gy. Otherwise, six locoregional failures were observed within irradiated volume receiving 70 Gy. Local and nodal control rates at 3 years were 91 and 89%, respectively. Adverse events were acceptable, and 25 (81%) of 31 patients who were alive without recurrence at 2 years had xerostomia of ≤Grade 1. The overall survival rate at 3 years was 87%. CONCLUSIONS Target definition along with anatomically defined boundaries was feasible without compromise of the therapeutic ratio. It is worth testing this method further to minimize the unnecessary irradiated volume and to standardize the target definition in intensity-modulated radiotherapy for nasopharyngeal cancer.